Heterocycle-fused pyrazolo[3,4-d]pyridin-3-ones as benzodiazepine receptor modulators

ABSTRACT

Disclosed are e.g. 2-aryl-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-ones, 2-aryl-thieno[2,3-b]pyrazolo[4,3-d]pyridin-3(5H)-ones, 2-aryl-pyrazolo[4,3-c][1,7]naphthyridin-3(5H)-ones, useful as benzodiazepine receptor modulators.

SUMMARY OF THE INVENTION

The present invention is directed to 2-substituted [b]-heterocycle-fusedpyrazolo[3,4-d]pyridin-3-ones of the formula IA or IB which arebenzodiazepine receptor ligands and modulators demonstrating usefulnervous system regulatory activity, e.g. psychoactive, such asanxiolytic, and anticonvulsant activity.

The foregoing attributes render compounds of this invention particularlyuseful when administered, alone or in combination, to mammals for thetreatment of e.g. nervous system disorders, such as anxiety, andconvulsive conditions (epilepsy). Compounds of the invention may also beuseful as antidepressants, as somnolytics, as appetite suppressants, asantagonists (antidotes) of the effects of benzodiazepine drugs on thecentral nervous system, as well as antagonists of the sedative effectsof alcohol and benzodiazepine drugs in combination.

DETAILED DISCLOSURE OF THE INVENTION

This invention relates to novel 2-substituted-[b]heterocycloe-fusedpyrazolo[3,4-d]-pyridin-3-ones, useful as e.g. benzodiazepine receptormolulators, processes for preparing the same, pharmaceuticalcompositions comprising said compounds and methods of treating e.g.nervous system disorders by administration of said compounds andcompositions to mammals.

Particularly the invention relates to compounds of formula IA or IB##STR1## wherein A represents a 3-membered bivalent residue completing afused five-membered unsaturated heterocyclic ring containing one sulfur,oxygen, or unsubstituted or lower alkyl substituted amino nitrogen atom,and wherein the carbon atoms in said residue are unsubstituted or one ofthem is substituted by lower alkyl, carbo-(lower)-alkoxy, halogen ortrifluoromethyl; or A represents a 3-membered bivalent residuecompleting a fused five-membered unsaturated heterocyclic ringcontaining two nitrogen atoms separated by a carbon atom, one of whichis unsubstituted or lower alkyl substituted amino nitrogen and the otheris imino nitrogen, and wherein the carbon atom is unsubstituted orsubstituted by lower alkyl, phenyl, or phenyl monosubstituted by loweralkyl, lower alkoxy, halogen or trifluoromethyl; or A represents a3-membered bivalent residue completing a fused five-membered unsaturatedheterocyclic ring containing one nitrogen atom and one oxygen or sulfuratom, and wherein the carbon atom in said residue is unsubstituted orsubstituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; orA represents a 4-membered bivalent residue completing a fusedsix-membered unsaturated heterocyclic ring containing one nitrogen atom,wherein the nitrogen atom is not directly attached to the β-carbon ofthe ring system, and wherein the carbon atoms in said residue areunsubstituted or substituted by one to three radicals selected fromlower alkyl, lower alkoxy, halogen and trifluoromethyl; or A representsa 4-membered bivalent residue completing a fused six-memberedunsaturated heterocyclic ring containing two nitrogen atoms, and thecarbon atoms in said residue are unsubstituted or substituted by one ortwo radicals selected from lower alkyl, lower alkoxy, halogen andtrifluoromethyl;

R₁ represents phenyl or phenyl substituted by one or two radicalsselected from lower alkyl, lower alkoxy, halogen and trifluoromethyl; orR₁ represents a five-membered unsaturated heterocyclic radicalcontaining one hetero atom selected from sulfur, oxygen andunsubstituted or lower alkyl substituted amino nitrogen, or a saidradical containing two hetero atoms consisting of one imino nitrogen andone member selected from unsubstituted or lower alkyl substituted aminonitrogen, sulfur and oxygen; or R₁ represents an unsaturated sixmembered heterocyclic radical containing one or two nitrogen atoms; orR₁ represents a bicyclic benzo-fused five membered unsaturatedheterocyclic radical containing one hetero atom selected from sulfur,oxygen and unsubstituted or lower alkyl substituted amino nitrogen; orR₁ represents a bicyclic benzo-fused five membered unsaturatedheterocyclic radical containing two hetero atoms consisting of one iminonitrogen and one member selected from unsubstituted or lower alkylsubstituted amino nitrogen, oxygen and sulfur; or R₁ represents abicyclic benzo-fused six membered unsaturated heterocyclic radicalcontaining one or two nitrogen atoms; or R₁ represents any of saidheterocyclic radicals mono- or di-substituted on carbon by lower alkoxy,lower alkyl or halogen;

R₂, R₃ and R₃ ' independently represent hydrogen or lower alkyl; ortautomers thereof; or salts thereof, particularly pharmaceuticallyacceptable salts.

Preferred are the compounds of formula IA or IB wherein A together withthe two carbon atoms to which it is attached represents a fusedunsaturated heterocyclic ring selected from (a) thieno, furo, andN-unsubstituted or N-lower alkyl substituted pyrrolo, wherein the carbonatoms in any of said rings are unsubstituted or one of them issubstituted by lower alkyl, carbo-(lower)-alkoxy, halogen ortrifluoromethyl; (b) N-unsubstituted or N-lower alkylsubstituted-imidazo, wherein the carbon atom in said ring isunsubstituted or substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; (c) thiazolo, oxazolo, isoxazolo, 2,3-, 3,4- or4,3-pyrido, and pyridazino, wherein the carbon atoms forming any of saidrings are unsubstituted or one or two are substituted by lower alkyl,lower alkoxy or halogen; (d) pyrimido and pyrazino wherein the carbonatoms in any of said rings are unsubstituted or one is substituted bylower alkyl or lower alkoxy; R₁ represents phenyl, or phenyl mono- ordisubstituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;or R₁ represents an aromatic heterocyclic radical selected from pyridyl,quinolyl, isoquinolyl, pyrimidyl and thiazolyl, or any said heterocyclicradical mono- or di-substituted by lower alkyl, lower alkoxy or halogen;and R₂, R₃ and R₃ ' independently represent hydrogen or lower alkyl; orpharmaceutically acceptable salts thereof.

The said above-cited compounds of formula IA or IB represent the R₁-substituted-(thieno, furo, pyrrolo, imidazo, thiazolo, oxazolo,isoxazolo, pyrido, pyridazino, pyrimido orpyrazino)-pyrazolo[2,3-d]pyridin-3-ones as defined above.

Particularly preferred are said compounds of formula IA or IB wherein Ais as above; R₂, R₃ and R₃ ' are hydrogen; and

(a) wherein R₁ is phenyl or phenyl mono-substituted by lower alkyl,lower alkoxy or halogen;

(b) wherein R₁ is 2-pyridyl, 5-(methyl, methoxy or chloro)-2-pyridyl,3-pyridyl, 6-(methyl or methoxy)-3-pyridyl or 4-pyridyl;

(c) wherein R₁ is 3-pyrimidyl, 5-(methyl, methoxy orchloro)-2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl;

(d) wherein R₁ is thiazolyl or 5-(methyl, methoxy orchloro)-2-thiazolyl;

(e) wherein R₁ is 2-quinolyl, 3-quinolyl, or 7-chloro-4-quinolyl; and

(f) wherein R₁ is 1-isoquinolyl; tautomers thereof; or pharmaceuticallyacceptable salts thereof.

One particular embodiment of the invention is directed topyrido-pyrazolo[3,4-d]pyridin-3-ones (namely pyrazolo[4,3-c][1,6], [1,7]or [1,8]-naphthyridin-3-ones) and is represented by compounds of formulaIA or IB wherein A together with the two carbon atoms to which it isattached represents fused 2,3-, 3,4- or 4,3-pyrido (preferably 3,4- or4,3-pyrido), or any of said pyrido rings mono- or di-substituted bylower alkyl, lower alkoxy or halogen; R₁, R₂, R₃ and R₃ ' have meaningas given above; or pharmaceutically acceptable salts thereof.

Another embodiment of the invention is directed tothieno-pyrazolo[3,4-d]pyridin-3-ones, and is represented by compounds offormula IA or IB wherein A together with the two carbon atoms to whichit is attached represents fused 2,3- or 3,2-thieno, and the carbon atomsin said thieno ring are unsubstituted or one is substituted by loweralkyl, carbo-(lower)-alkoxy, halogen or trifluoromethyl; R₁, R₂, R₃ R₃ 'have meaning as given above; or pharmaceutically acceptable saltsthereof.

Another embodiment of the invention is directed toimidazo-pyrazolo[3,4-d]pyridin-3-ones, and is represented by compoundsof formula IA or IB wherein A together with the two carbon atoms towhich it is attached represents fused N-unsubstituted or N-lower alkylsubstituted 5,4-imidazo, and the carbon atoms in said 5,4-imidazo ringis unsubstituted or substituted by lower alkyl, phenyl or phenylmono-substituted by lower alkyl, lower alkoxy, halogen, ortrifluoromethyl; R₁, R₂, R₃ and R₃ ' have meanings as given above; orpharmaceutically acceptable salts thereof.

Further preferred are the said pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-ones of formula II ##STR2## wherein R₁ representsphenyl or phenyl mono- or di-substituted by lower alkyl, lower alkoxy,halogen or trifluoromethyl; or R₁ represents an aromatic heterocyclicradical selected from pyridyl, quinolyl, isoquinolyl, pyrimidyl andthiazolyl, or any said radical mono- or disubstituted by lower alkyl,lower alkoxy or halogen; R₄ and R₅ represent independently hydrogen,lower alkyl, lower alkoxy or halogen; or tautomers thereof; orpharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula II

(a) wherein R₁ is phenyl or phenyl mono-substituted by lower alkyl,lower alkoxy or halogen; R₄ is hydrogen, methoxy, methyl, fluoro orchloro; R₅ is hydrogen; or tautomers thereof; or pharmaceuticallyacceptable salts thereof.

(b) wherein R₁ is 2-pyridyl, 5-(methyl, methoxy or chloro)-2-pyridyl,3-pyridyl, 6-(methyl or methoxy)-3-pyridyl or 4-pyridyl; R₄ is hydrogen,methyl, methoxy, fluoro or chloro; R₅ is hydrogen; or tautomers thereof;or pharmaceutically acceptable salts thereof.

(c) wherein R₁ is 2-pyrimidyl, 5-(methyl, methoxy orchloro)-2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl; R₄ is hydrogen,methoxy, methyl, fluoro or chloro; R₅ is hydrogen; or tautomers thereof;or pharmaceutically acceptable salts thereof.

(d) wherein R₁ is 2-thiazolyl or 5-(methyl, methoxy orchloro)-2-thiazolyl; R₄ is hydrogen, methoxy, methyl, fluoro or chloro;R₅ is hydrogen; or tautomers thereof; or pharmaceutically acceptablesalts thereof.

(e) wherein R₁ is 2-quinolyl, 3-quinolyl, or 7-chloro-4-quinolyl; R₄ ishydrogen, methyl, fluoro or chloro; R₅ is hydrogen; or tautomersthereof; or pharmaceutically acceptable salts thereof; and

(f) wherein R₁ is 1-isoquinolyl; R₄ is hydrogen, methoxy, methyl, fluoroor chloro; R₅ is hydrogen; or tautomers thereof; or pharmaceuticallyacceptable salts thereof.

Also preferred are the pyrazolo [4,3-c][1,7]naphthyridin-3-ones offormula III ##STR3## wherein R₁ represents phenyl or phenyl mono- ordi-substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;or R₁ represents an aromatic heterocyclic radical selected from pyridyl,quinolyl, isoquinolyl, pyrimidyl and thiazolyl, or any said radicalmono- or disubstituted by lower alkyl, lower alkoxy or halogen; R₆ andR₇ represent independently hydrogen, lower alkyl, lower alkoxy orhalogen; or tautomers thereof; or pharmaceutically acceptable saltsthereof.

Particularly preferred are compounds of formula III

(a) wherein R₁ is phenyl or phenyl mono-substituted by lower alkyl,lower alkoxy or halogen; R₆ is hydrogen, methoxy, methyl, fluoro orchloro; R₇ is hydrogen; or tautomers thereof; or pharmaceuticallyacceptable salts thereof.

(b) wherein R₁ is 2-pyridyl, 5-(methyl, methoxy or chloro)-2-pyridyl,3-pyridyl, 6-(methyl or methoxy)-3-pyridyl or 4-pyridyl; R₆ is hydrogen,methyl, methoxy, fluoro or chloro; R₇ is hydrogen; or tautomers thereof;or pharmaceutically acceptable salts thereof.

(c) wherein R₁ is 2-pyrimidyl, 5-(methyl, methoxy orchloro)-2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl; R₆ is hydrogen,methoxy, methyl, fluoro or chloro; R₇ is hydrogen, or tautomers thereof;or pharmaceutically acceptable salts thereof; and

(d) wherein R₁ is 2-thiazolyl or 5-(methyl, methoxy orchloro)-2-thiazolyl; R₆ is hydrogen, methoxy, methyl, fluoro or chloro;R₇ is hydrogen; or tautomers thereof; or pharmaceutically acceptablesalts thereof.

Also preferred are the thieno[2,3-b]pyrazolo[3,4-d]pyridin-3-ones offormula IV ##STR4## wherein R₁ represents phenyl or phenyl mono- ordi-substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;or an aromatic heterocyclic radical selected from pyridyl, quinolyl,isoquinolyl, pyrimidyl and thiazolyl, or any said heterocyclic radicalmono- or disubstituted by lower alkyl, lower alkoxy or halogen; R₈represents hydrogen, lower alkyl, carbo-(lower)alkoxy, halogen ortrifluoromethyl; or tautomers thereof; or pharmaceutically acceptablesalts thereof.

Particularly preferred are compounds of formula IV

(a) wherein R₁ is phenyl or phenyl mono-substituted by lower alkyl,lower alkoxy or halogen; or tautomers thereof; or pharmaceuticallyacceptable salts thereof.

(b) wherein R₁ is 2-pyridyl, 5-(methyl, methoxy or chloro)-2-pyridyl,3-pyridyl, 6-(methyl or methoxy)-3-pyridyl or 4-pyridyl; R₈ is hydrogenor halogen; or tautomers thereof; or pharmaceutically acceptable saltsthereof; and

(c) wherein R₁ is 2-thiazolyl or 5-(methyl, methoxy orchloro)-2-thiazolyl; R₈ is hydrogen or halogen; or tautomers thereof; orpharmaceutically acceptable salts thereof.

Also preferred are thieno[3,2-b]pyrazolo[3,4-d]pyridin-3-ones of formulaV ##STR5## wherein R₁ represents phenyl or phenyl mono- ordi-substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;or an aromatic heterocyclic radical selected from pyridyl, quinolyl,isoquinolyl, pyrimidyl and thiazolyl, or any said heterocyclic radicalmono- or disubstituted by lower alkyl, lower alkoxy or halogen; R₉represents hydrogen, lower alkyl, carbo-(lower)alkoxy, halogen ortrifluoromethyl; or tautomers thereof; or pharmaceutically acceptablesalts thereof.

Particularly preferred are compounds of formula V:

(a) wherein R₁ is phenyl or phenyl mono-substituted by lower alkyl,lower alkoxy or halogen; R₉ is hydrogen or halogen; or tautomersthereof; or pharmaceutically acceptable salts thereof; and

(b) wherein R₁ is 2-pyridyl, 5-(methyl, methoxy or chloro)-2-pyridyl,3-pyridyl, 6-(methyl or methoxy)-3-pyridyl or 4-pyridyl; R₉ is hydrogenor halogen; or tautomers thereof; or pharmaceutically acceptable saltsthereof.

Also preferred are the imidazo[4,5-b]pyrazolo[3,4-d]pyridin-3-ones offormula VI ##STR6## wherein R₁ represents phenyl or phenyl mono- ordi-substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;or an aromatic heterocyclic radical selected from pyridyl, quinolyl,isoquinolyl, pyrimidyl and thiazolyl, or any said heterocyclic radicalsubstituted by lower alkyl, lower alkoxy or halogen; R₂ representshydrogen or lower alkyl; R₁₀ represents hydrogen, lower alkyl, phenyl orphenyl monosubstituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R₁₁ represents hydrogen or lower alkyl; or tautomersthereof; or pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula VI:

(a) wherein R₁ is phenyl or phenyl mono-substituted by lower alkyl,lower alkoxy or halogen; R₂, R₁₀ and R₁₁ are independently hydrogen ormethyl; or tautomers thereof; or pharmaceutically acceptable saltsthereof; and

(b) wherein R₁ is 2-pyridyl, 5-(methyl, methoxy or chloro)-2-pyridyl,3-pyridyl, 6-(methyl or methoxy)-3-pyridyl or 4-pyridyl; R₂, R₁₀ and R₁₁are independently hydrogen or methyl; or tautomers thereof; orpharmaceutically acceptable salts thereof.

The general definitions used herein have the following meaning withinthe scope of the present invention.

The term "lower" referred to above and hereinafter in connection withorganic radicals or compounds respectively defines such with up to andincluding 7, preferably up and including 4 and advantageously one or twocarbon atoms.

Halogen is preferably fluoro or chloro, but may also be bromo or iodo.

A lower alkyl group or such present in said lower alkoxy, or otheralkylated groups, is above all methyl, but also ethyl, n- or i-(propyl,butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methylbutyl.Carbo(lower)alkoxy represents lower alkoxycarbonyl, e.g. ethoxy- ormethoxycarbonyl.

Pyridyl represents 2-,3- or 4-pyridyl, advantageously 3-pyridyl.

Quinolyl represents preferably 2-, 3- or 4-quinolyl, advantageously3-quinolyl.

Isoquinolyl represents preferably 1-, 3- or 4-isoquinolyl,advantageously 1-isoquinolyl.

Pyrimidyl represents 2-, 4- or 5-pyrimidyl, preferably 2- or5-pyrimidyl.

Thiazolyl represents preferably 2-thiazolyl.

The compounds of the invention wherein R₃ and R₃ ' are hydrogen may berepresented by either of the tautomeric structure IA or IB, preferablystructure IA; furthermore said 3-oxo compounds may, under certainconditions, also exist as the 3-hydroxy tautomers; all of thesetautomers are within the scope of the present invention. Said compoundsform, especially in the form of the 3-hydroxy compounds, salts withstrong bases, and the salts are preferably alkali metal, e.g. sodium orpotassium salts of the 1- or 5-unsubstituted compounds (R₃ and R₃ '═H).

Furthermore the compounds of Formula IA or IB, form acid addition salts,which are preferably such of pharmaceutically acceptable inorganic ororganic acids, such as strong mineral acids, for example hydrohalic,e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitricacid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. acetic,propionic, succinic, glycolic, lactic, malic, tartaric, gluconic,citric, maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, benzoic,4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic,4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid; or ascorbicacid.

The compounds of the invention exhibit valuable pharmacologicalproperties, e.g. nervous system regulatory effects, by inter aliamodulating the benzodiazepine receptor activity in mammals. Thecompounds are thus useful for the treatment of nervous system diseases,e.g. those responsive to benzodiazepine receptor modulation.

The compounds of the invention bind to the benzodiazepine receptor andexhibit e.g. anxiolytic and/or anticonvulsant effects, or antagonism ofthe effects of benzodiazepine drugs. Said effects are demonstrable by invitro and in vivo tests, using advantageously mammals, e.g. mice, rats,or monkeys, as test objects. Said compounds can be applied to thementerally or parenterally, advantageously orally, or subcutaneously,intravenously or intraperitoneally, for example, within gelatin capsulesor in the form of starchy suspensions or aqueous solutions orsuspensions respectively. The applied dosage may range between 0.1 and100 mg/kg/day, preferably between about 0.1 and 50 mg/kg/day,advantageously between about 1 and 30 mg/kg/day.

The benzodiazepine receptor binding properties indicative of the nervoussystem regulatory activity of said new compounds are determined in thereceptor binding assay in vitro, e.g. as described in Nature 266, 732(1977) or Proc. Nat. Acad. Sci. USA 74, 3805 (1977). Diazepam bindsspecifically and with high affinity to crude synaptosomal membranepreparations from rat fore-brain. This binding is inhibited by otheranxiolytic compounds. When tritiated diazepam is used, the interactionof other drugs with said receptor can be readily assessed thus:membranes from rat fore-brain are incubated at 0°-5° for 30 minutes with2 nM tritiated diazepam and various concentrations of the test substancein a buffer medium maintained at pH 7.5. Solutions of the variousconcentrations of test substances are prepared by dilution of a 4.2 mMstock solution in dimethylacetamide-ethanol (1:10) with 50 mM pH 7.5Tris-HCl buffer. The membranes, containing the receptors with variousamounts of tritiated diazepam, are filtered onto glass fiber filters,which are then analyzed in a liquid scintillation counter. Theconcentration of the compounds of this invention, required to inhibitthe specific binding of 2 nM of tritiated diazepam by 50%, i.e. theIC₅₀, is determined graphically.

In vivo benzodiazepine receptor binding is determined essentially asdescribed in Eur. J. Pharmacol. 48, 213 (1978) and Nature 275, 551(1978).

Test compounds in a corn starch vehicle are administered orally orintraperitioneally to mice or rats. Thirty minutes later,3H-flunitrazepam (2 mmoles/Kg in saline) is injected into the tail vein,and the animals are sacrificed 20 minutes after injection of theflunitrazepam. The brains are then assayed by determining radioactivityin a liquid scintillation counter for binding of the radioligand to thereceptors. A decrease in the binding of 3H-flunitrazepam in thedrug-treated animals (as compared with the binding observed in animalstreated with vehicle alone) is indicative of benzodiazepine receptorbinding by the test compound.

Anxiolytic effects are observed, for example, according to theCook-Davidson conflict procedure, using male Wistar rats which aremaintained at 80% of normal body weight by dietary-, but notwater-restriction. They are trained to press a lever within aconditioning chamber, also containing a liquid dipper, a house light, aspeaker and a grid-floor. Both lever and grid are connected to anelectrical shock source and the chamber is situated in asound-attenuated room in which a white noise-source is activated duringtesting, in order to mask any extraneous auditory cues. Each session of47 minutes duration consists of two alternating schedules. The first isa Variable Interval (VI) schedule of 30 seconds, lasting for 5 minutes,during which a sweetened, condensed milk reinforcement is deliveredfollowing the first lever-press after an average of 30 seconds haveelapsed, and a drug-induced decrement of this performance is taken as anindication of a neurological deficit. Immediately following theVI-schedule both a 1000 Hz tone and a light-cue are activated,indicating the commencement of the second Fixed Ratio (FR) schedule,lasting for 2 minutes, wherein the milk reinforcement is deliveredconcomitant with an electric foot shock immediately following the tenthresponse, thereby establishing a conflict situation. The intensity ofsaid shock ranges between 2.0 and 3.6 mA, varying with each animal, inorder to adjust them to about 25-100 responses during this schedule overthe entire session. A drug-induced enhancement of performance during theFR-schedule is taken as indication of antianxiety effects. Thisincreased performance is measured by the increased number of electricfoot shocks taken during six FR sessions lasting 2 minutes each.

Anticonvulsant effects are observed, for example in the standardMetrazole (pentylenetetrazole) and maximal electroshock tests forassessing anticonvulsant activity, e.g. orally in the rat.

Male Wistar rats (130-175 g) are fasted for 18 hours but allowed waterad libitum prior to testing. The test compound is administered in acornstarch vehicle by oral intubation in a volume of 10 ml/Kg of bodyweight. One hour after administration of the test compounds, the animalsare administered intravenously (caudal vein) a dose of 24 mg/Kg ofMetrazole in water in a volume of 2.5 ml/Kg of body weight. The rats areimmediately placed in plexiglas cylinders and observed for clonicseizures of at least 5 seconds duration during the next 60 seconds. TheED₅₀ is the dose at which half the animals are protected from Metrazoleinduced clonic seizures during the observation periods.

Benzodiazepine antagonism is measured by the antagonism of theanticonvulsant activity of diazepam in the rat Metrazole model. Diazepam(5.4 mg/kg/po) and test compound are administered 1 hour before theMetrazole challenge.

In the maximal electroshock procedure for assessing anticonvulsantactivity in rats, seizures are induced by applying 150 mA of electriccurrent for 0.2 sec through corneal electrodes two hours after oraladministration of test compound as described for the Metrazole testabove. The ED₅₀ is the dose at which half the animals are protected fromelectroshock induced seizures during the 5 seconds observation period.

Illustrative of the invention the compounds of examples 2, 5a and 9exhibit an IC₅₀ of about 0.2 nM, 3 nM and 9 nM respectively in the invitro benzodiazepine receptor assay. Furthermore, e.g. the compound ofexample 1 inhibits flunitrazepam binding by about 75% in vivo at a doseof 30 mg/kg p.o. in the mouse.

The compounds of the invention also act as adenosine antagonists. Suchactivity is assessed by determination of inhibition of adenosineactivation of adenylate cyclase in vesicular preparations from guineapig brains, essentially as described in J. Neurochem. 22, 1031 (1974).

Accordingly, the compounds of the invention are useful nervous systemactive agents, e.g. as benzodiazepine receptor modulators for example inthe treatment or management of nervous systems disorders such asanxiety, convulsive conditions (epilepsy) and depression in mammals.They are also useful intermediates in the preparation of other valuableproducts, especially of pharmacologically active pharmaceuticalcompositions.

The compounds of the invention, the compounds of formula IA or IB andsalts, derivatives or tautomers thereof, are advantageously prepared bymethods known per se, according to the following processes:

(a) reacting a compound of formula VII ##STR7## wherein A, R₂ and R₃have meaning as previously defined and Y is lower alkoxy with a compoundof the formula VIII

    R.sub.3 '--NH--NH--R.sub.1                                 (VIII)

wherein R₁ has meaning as previously defined, and R₃ ' is hydrogen;

(b) reacting a compound of the formula IX ##STR8## wherein A and R₂ havemeaning as previously defined; X represents reactive etherified oresterified hydroxy; and Y represents lower alkoxy; with a compound offormula VIII wherein R₁ has meaning as previously defined, and R₃ 'represents hydrogen or lower alkyl;

(c) ring closing a compound of formula IX wherein X is --NR₃ '--NHR₁ andY is lower alkoxy or hydroxy; or X is hydroxy, reactive esterified oretherified hydroxy and Y is --NR₁ NHR₃ '; and wherein A, R₁, R₂ and R₃ 'have meaning as previously defined; and if desired, converting aresulting compound of formula IA or IB into another compound of theinvention; and, if desired, converting a resulting compound of formulaIA or IB into a salt thereof or liberating a free compound from such asalt.

The compounds of the invention may also be prepared analogous to othermethods known per se, e.g. those disclosed in U.S. Pat. No. 4,312,870.

The condensation according to process (a) is carried out preferably at atemperature range of about 50° to 180°, advantageously in the presenceof inert solvents such as aliphatic or aromatic hydrocarbons and etherssuch as toluene, xylene, biphenyl and/or diphenyl ether, advantageouslye.g. while distilling off the alkanol and water generated, or in thepresence of dehydrating agents, such as molecular sieves.

The starting materials of formula VII are known or may be prepared bymethods well-known to the art, e.g. according to e.g. U.S. Pat. No.3,429,887 and the examples herein.

The starting materials of formula VIII are also known or are prepared bymethods well known to the art.

The condensation according to process (b) above is carried out with anexcess or equivalent amount of a compound of formula VIII advantageouslyand depending on the nature of the reactants at temperatures betweenabout 50° and 200° and preferably in an inert solvent e.g. a loweralkanol such as amyl alcohol, n-butyl alcohol or ethanol, an aliphaticor aromatic hydrocarbon such as toluene, xylene and biphenyl, anaromatic ether, such as diphenyl ether or mixtures thereof.

The starting materials of formula IX are known or are prepared bymethods well known to the art, e.g. according to U.S. Pat. No. 3,786,043and the examples herein.

In starting materials of formula IX and IXa below, when X representsreactive esterified hydroxy said group is preferably halogen such aschloro or bromo or, lower alkylsulfonyloxy such as methanesulfonyloxy orwhen X represents reactive etherified hydroxy said group is preferablylower alkoxy such as methoxy, or aryloxy such as phenoxy.

The ring closure of compounds of formula IX according to process (c) iscarried out preferably at a temperature range of about 50° to 200°,advantageously in the presence of inert solvents such as aliphatic oraromatic hydrocarbons, such as toluene, xylene or biphenyl, ethers suchas diphenyl ether, alkanols such as n-butanol, with or without a base(such as an alkali metal alkoxide, e.g. sodium ethoxide), a dehydratingagent (such as molecular sieves) or a condensing agent (such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), depending on the natureof X and Y.

Advantageously a condensing agent or dehydrating agent is used for thering closure of compounds of formula IX wherein Y represents hydroxy.

The starting materials for process (c) of formula IX wherein X is --NR₃'--NHR₁ and Y is lower alkoxy or hydroxy may be obtained by condensationof a compound of formula IX wherein X represents reactive etherified oresterified hydroxy and Y represents lower alkoxy with a hydrazine offormula VIII, wherein R₁ and R₃ ' are as previously defined, in an inertsolvent, preferably at a temperature range of about 0° to 75°, andhydrolysis if so required.

The hydrazide starting materials of formula IX wherein X is hydroxy,esterified or etherified hydroxy and Y is --NR₁ NHR₃ ' areadvantageously prepared by condensing a compound of formula IXa ##STR9##wherein X represents hydroxy, esterified or etherified hydroxy, COY'represents a reactive functionalized carboxy group (such as an acidhalide or a mixed anhydride group) and A and R₂ are as previouslydefined, with a hydrazine of formula VIII or with an NHR₃ '-acylatedderivative thereof (such as HNR₁ --NR₃ '--COCF₃) wherein R₁ and R₃ ' areas previously defined, and subsequently deacylating the resulting acylsubstituted hydrazide.

A preferred starting material of formula IXa is the appropriatelyring-fused and substituted compound of formula IXa wherein X and Y'represent chloro.

The compounds of the invention so obtained can be converted into othercompounds of formula IA or IB according to known methods.

For example compounds of formula IA or IB with R₃ or R₃ '=H can be1-substituted with reactive esters of R₃ --OH, e.g. such of hydrohalic,aliphatic or aromatic sulfonic acids, such as R₃ -(halides, sulfates,aliphatic or aromatic sulfonates), e.g. methyl iodide, dimethyl sulfate,methyl mesylate or tosylate, in order to yield the 1-substitutedcompounds of Formula IB. Those of Formula IA are similarly obtained fromthe corresponding alkali metal salts, e.g. the sodium salt, whereby5-substitution occurs. The metal derivative intermediates are obtainedby metallation with reactive organometallic agents such as lithiumdiisopropylamide, with alkali metal alkoxides such as sodium methoxide,or thallous ethoxide, or alkali metal hydrides such as sodium orpotassium hydride.

Finally, the compounds of the invention are either obtained in the freeform, or as a salt thereof whenever applicable. Any resulting free basecan be converted into a corresponding acid addition salt, preferablywith the use of a pharmaceutically acceptable acid or anion exchangepreparation, or any resulting salt can be converted into thecorresponding free base, for example, with the use of a stronger base,such as a metal or ammonium hydroxide or a basic salt, e.g. an alkalimetal hydroxide or carbonate, or a cation exchange preparation. Saidacid addition salts are preferably such of pharmaceutically acceptableinorganic or organic acids described previously.

Compounds of formula IA or IB with R₃ or R₃ ' being hydrogen can also beconverted into the corresponding metal salts by e.g. treatment with thealkaline or alkaline earth metal hydroxides or carbonates.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds including their salts, can also be obtained in the form oftheir hydrates or include other solvents used for crystallization.

In case mixtures of isomers of any the above compounds, e.g. of formulaI to IX are obtained, these can be separated into the single isomers bymethods in themselves known, e.g. by fractional distillation,crystallization and/or chromatography.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably nearthe boiling point of the solvents used, at atmospheric orsuperatmospheric pressure.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or theprocess is discontinued at any stage thereof, or in which the startingmaterials are formed under the reaction conditions, or in which thereaction components are used in the form of their salts or pure isomers.Mainly those starting materials should be used in said reactions, thatlead to the formation of those compounds, indicated above as beingespecially valuable.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine; (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol; for tablets, also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, or effervescent mixtures; and/or(e) absorbents, colorants, flavors and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Said compositions are prepared according toconventional mixing, granulating or coating methods, respectively, andcontain about 0.1 to 75%, preferably about 1 to 50%, of the activeingredient. A unit dosage for a mammal of about 50 to 70 Kg weight maycontain between about 5 and 100 mg of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures hereinare given in degrees Centigrade, and all parts whenever given are partsby weight. If not mentioned otherwise, all evaporations are performedunder reduced pressure, preferably between about 15 and 100 mm Hg.Proportions whenever given for liquids are in parts by volume.

EXAMPLE 1

A solution of 2.60 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylateand 1.25 g of phenylhydrazine in 32 ml of methanol is stirred at 22° for18 hours, then refluxed for 3 hours. The resultant slurry is allowed tocool down to room temperature and filtered, obtaining2-phenyl-pyrazolo[4,3-c][1,6]-naphthyridin-3(5H)-one hydrochloride, mp310°; IR (KBr) 750, 756, 777, 802, 843 cm⁻¹. This hydrochloride salt isdissolved in 1N sodium hydroxide and filtered. Ammonium chloride (10 g)is added to the filtrate, the resulting precipitate is collected, and iscrystallized from methanol to yield the free base,2-phenyl-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one, m.p. 334°-337°.

The starting material is prepared as follows:

A mixture of 9.3 g of ethyl 4-hydroxy-1,6-naphthyridine-3-carboxylate(prepared according to J. Org. Chem. 15, 1224 (1950)) and 56 ml ofphosphorous oxychloride is refluxed for 2 hours 40 minutes, thenevaporated to dryness and the residue is treated with cold diluteammonium hydroxide and methylene chloride. Insoluble material is removedby filtration, then organic layer is separated, washed with brine, driedover sodium sulfate and evaporated to dryness to yield ethyl4-chloro-1,6-naphthyridine-3-carboxylate.

EXAMPLE 2

A solution of 3.8 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylateand 1.82 g of p-chlorophenylhydrazine in 30 ml of methanol is stirred at22° for 3 hours, then refluxed for 3 and a half hours. The reactionmixture is then allowed to cool down to room temperature, and filteredcollecting 2-p-chlorophenyl-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-onehydrochloride, m.p. above 345°; IR (KBr) 776, 813, 823, 842, 896 cm⁻¹.This hydrochloride salt is converted to the corresponding free base inthe same manner as described in Example 1, m.p. above 360°; IR (KBr)748, 764, 785, 790, 825, 840, 895 cm⁻¹.

EXAMPLE 3

To a slurry of 1.5 g of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate(prepared according to J. Inorg. Nucl. Chem., (1966) 28, 2439) in 17 mlof dimethylformamide is added 0.907 g of oxalyl chloride in 2 ml ofmethylene chloride while maintaining the reaction temperature between-25° and -30°. The mixture is stirred at -25° for 35 minutes. A solutionof 0.995 g of diisopropylethylamine and 0.833 g of phenylhydrazine in 4ml of methylene chloride is added to the mixture in 8 minutes at -30° to-25°. The mixture is then stirred for 30 minutes at -25°, 20 minutes at0° and 40 minutes at 23°. The resultant dark purple solution is pouredinto 60 ml of water. Dark precipitate is collected, washed with waterand crystallized from methanol to yield 2-phenyl-pyrazolo[4,3-c][1,5]naphthyridin-3(5H)-one, m.p. 314°-316°.

EXAMPLE 4

A suspension of ethyl4-[2-(4-pyridyl)hydrazino]-1,6-naphthyridin-3-carboxylate hydrochloride(1.76 g) in 50 ml of n-butanol is refluxed for 20 hours. The mixture iscooled down to room temperature and filtered. Collected solid isdissolved in aqueous sodium hydroxide and stirred at room temperaturefor 21 hours, then filtered. The filtrate is acidified with 1Nhydrochloric acid to precipitate a solid, which is collected, washedsuccessively with aqueous methanol, methanol and acetone to yield2-(4-pyridyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one hydrochloride,m.p. above 345°; IR (KBr) 726, 746, 791, 833, 898 cm⁻¹.

The starting material is prepared as follows:

A solution of 2.36 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylateand 1.53 g of 4-hydrazinopyridine hydrochloride in 37 ml of methanol isstirred for 19 hours at room temperature, then refluxed for 4 hours. Thereaction mixture is then cooled in an ice bath, and solid is collectedby filtration, washed successively with methanol and ether to yieldethyl 4-[2-(4-pyridyl)hydrazino]-1,6-naphthyridine-3-carboxylatehydrochloride.

EXAMPLE 5

(a) A solution of 2.84 g of ethyl4-chloro-1,6-naphthyridine-3-carboxylate and 1.35 g of3-hydrazinopyridine in 36 ml of methanol is stirred at room temperaturefor 2.5 hours, then refluxed for 4.5 hours, then cooled in an ice bathand filtered. Collected solid is washed with methanol, then with etherto yield 2-(3-pyridyl)pyrazolo[4,3-c][1,6]naphthyridin-3-(5H)-onehydrochloride, m.p. 302°-305°.

(b) In an analogous manner, from 2.6 g of ethyl4-chloro-1,6-naphthyridine-3-carboxylate and 1.34 g of2-hydrazino-thiazole (prepared according to Can. J. Chem. 1970, 48,3554), there is obtained2-(2-thiazolyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-onehydrochloride, m.p. above 345°; IR (KBr) 730, 746, 786, 811, 854 cm⁻¹.

EXAMPLE 6

A solution of 1.75 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylateand 1.17 g of 2-hydrazinopyrimidine hydrochloride (prepared according toYakugakuzasshi, 1953, 73, 598) in 60 ml of n-butanol is refluxed for 3hours. The resultant slurry is cooled to room temperature and filtered.Collected solid is washed with ethanol, then with ether to yield2-(2-pyrimidyl)pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one hydrochloride,m.p. above 350°; IR (KBr) 782, 791, 820, 830, 871 cm⁻¹.

EXAMPLE 7

A mixture of 3.0 g of ethyl4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate (prepared according toU.S. Pat. No. 3,786,043) and 1.42 g of phenylhydrazine in 30 ml ofn-butanol is refluxed for 18 hours. The mixture is chilled in an icebath and filtered to give a solid which is taken up in 50 ml of 1Nsodium hydroxide and sufficient water to dissolve. The resultingsolution is filtered to remove insoluble, washed with ether andneutralized with 3.0 g of ammonium chloride. The resulting mixture isfiltered collecting a solid which is washed with water and dried toyield 7-methyl-2-phenylpyrazolo[4,3-c][1,8]naphthyridin-3(5H)-onehemihydrate, m.p. 305°-308°.

EXAMPLE 8

A mixture of 2.25 g of ethyl4-chloro-6,8-dimethoxy-1,7-naphthyridin-3-carboxylate and 1.2 g ofp-chlorophenylhydrazine in 180 ml of xylene is heated at refluxovernight, then cooled and extracted with 1N sodium hydroxide (300 ml).The aqueous alkali phase is separated, washed with ether and neutralizedwith 20 g of ammonium chloride to precipitate a solid. The solid iscollected and washed with ethanol to yield2-(4-chlorophenyl)-6,8-dimethoxy-pyrazolo[4,3-c][1,7]naphthyridin-3(5H)-one,m.p. 318°-321°.

The starting material is prepared as follows:

A mixture of 5.6 g of 3-amino-2,6-dimehthoxypyridine and 8.8 g ofdiethyl ethoxymethylenemalonate is stirred at room temperature overnightto form a solid. The solid is collected, dissolved in ethyl acetate,treated with decolorizing charcoal and evaporated to dryness to yielddiethyl N-[3-(2,6-dimethoxypyridyl)]-aminomethylenemalonate, m.p.78°-81°.

Diethyl N-[3-(2,6-dimethoxypyridyl)]-aminomethylenemalonate (12.5 g) in250 ml of an eutectic mixture of diphenyl ether and biphenyl (Dowtherm®)is heated at reflux for 5 hours under nitrogen atmosphere, then cooledto room temperature to deposit a solid. The solid is collected andwashed with ether to yield ethyl4-hydroxy-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate, m.p. 311°(dec.).

A solution of 3.5 g of oxalyl chloride in 5 ml of dry acetonitrile isadded dropwise to anhydrous dimethylformamide at -30°. After 20 minutes,7.0 g of ethyl 4-hydroxy-6,8-dimethoxy-1,7-naphthyridine-3-carboxylateis added at -30°. Reaction temperature is kept between -20° and -30° for30 minutes, then allowed to warm up to room temperature and evaporatedto dryness. Residue is taken up in chloroform, washed with cold sodiumbicarbonate aqueous solution, dried over magnesium sulfate, treated withdecolorizing charcoal and evaporated to dryness to yield ethyl4-chloro-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate, m.p. 200°-210°.

EXAMPLE 9

A mixture of 3.2 g of ethyl 4-chloro-thieno[2,3-b]pyridine-3-carboxylate(prepared according to J. Heterocyclic Chem., 1977, 14, 807) and 2.08 gof 4-chlorophenylhydrazine in 50 ml of n-butanol is refluxed for 48hours. The reaction mixture is cooled in an ice bath and the resultingprecipitate is collected, washed with a small amount of n-butanol toyield a solid. The solid is treated with ether and 1N sodium hydroxide(20 ml) and water (50 ml). The aqueous phase is washed with ether, thenneutralized with ammonium chloride (2 g) to precipitate a yellow solid.The solid is collected, washed with water and dried to yield2-(4-chlorophenyl)-thieno[2,3-b]pyrazolo[3,4-d]pyridin-3(5H)-onehydrate, m.p. 310°-313°.

EXAMPLE 10

Compounds which are prepared analogous to the methods illustrated by theprevious examples:

EXAMPLE

10(a)2-(4-Chlorophenyl)-7-methyl-pyrazolo[4,3-c][1,8]-naphthyridin-3(5H)-one2/3 hydrate, m.p. 340°-342°.

10(b) 7-Methyl-2-(3-pyridyl)-pyrazolo[4,3-c][1,8]naphthyridin-3(5H)-onehydrate, m.p. 314°-317°.

10(c)7-Methyl-2-(2-pyrimidyl)-pyrazolo[4,3-c][1,8]naphthyridin-3(5H)-onehydrochloride hemihydrate, m.p. 310°-315°.

10(d)6,8-Dimethoxy-2-phenyl-pyrazolo[4,3-c][1,7]-naphthyridin-3(5H)-one, m.p.303°-306°.

EXAMPLE 11

Compounds of formulae I, II, III, IV, V and VI which can be preparedanalogous to the methods illustrated by the previous examples:

    ______________________________________                                        Example Formula  R.sub.1       Other Substituents                             ______________________________________                                        11/a    II       4-pyrimidyl   7-methyl                                       11/b    III      6-Me--3-pyridyl                                                                             --                                             11/c    III      2-quinolyl    8-methyl                                       11/d    IV       5-MeO--2-pyrimidyl                                                                          7-methyl                                       11/e    V        5-chloro-2-thiazolyl                                                                        7-chloro                                       11/f    VI       5-chloro-2-pyridyl                                                                          4,6-dimethyl                                   11/g    VI       5-pyrimidyl   4,6,7-trimethyl                                11/h    VI       4-chlorophenyl                                                                              --                                             11/i    III      p-chlorophenyl                                                                              --                                             ______________________________________                                        Starting Materials:                                                           Example                                                                       11/a   4-Hydrazinopyrimidine, J. Chem. Soc., 1955, 3478.                      11/b   Ethyl 4-chloro-1,7-naphthyridine-3-carboxylate from                           ethyl 4-hydroxy-1,7-naphthyridin-3-carboxylate 7-oxide                        of J. Org. Chem., 19, 2008 (1954)                                      11/c   Ethyl 4-chloro-6-methyl-1,7-naphthyridine-3-carbo-                            xylate from ethyl 4-hydroxy-6-methyl-1,7-naphthy-                             ridine-3-carboxylate of U.S. Pat. No. 3,429,887.                       11/d   5-Methoxy-2-hydrazinopyrimidine from 2-chloro-5-                              methoxy-pyrimidine, of J. Chem. Soc., 1960, 4590.                             Ethyl 4-chloro-2-methyl-thieno[2,3-b]pyridine-5-                              carboxylate from ethyl 4-hydroxy-2-methyl-thieno[2,                           3-b]-pyridine-5-carboxylate of U.S. Pat. No. 3,997,545.                11/e   Ethyl 2,7-dichloro-thieno[3,2-b]pyridine-6-carboxylate                        of European patent application 46,990.                                 11/f   Ethyl 7-chloro-3,5-dimethyl-imidazo[4,5-b]pyridine-                           6-carboxylate of J. heterocyclic Chem., 14, 813 (1977).                11/g   Ethyl 7-chloro-2,3,5-trimethyl-imidazo[4,5-b]pyridine-                        6-carboxylate of J. Heterocyclic Chem., 14, 813 (1977).                ______________________________________                                    

EXAMPLE 12

Preparation of 10,000 tablets each containing 10 mg of the activeingredient:

    ______________________________________                                        2-(3-pyridyl)-pyrazolo[4,3-c][1,6]                                                                   100.00 g                                               naphthyridin-3(5h)--one hydrochloride                                         Lactose                1,157.00 g                                             Corn Starch            75.00 g                                                Polyethylene glycol 6,000                                                                            75.00 g                                                Talcum powder          75.00 g                                                Magnesium stearate     18.00 g                                                Purified water         q.s.                                                   ______________________________________                                    

PROCEDURE

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance, lactose, talcum, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 40 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 150 ml of water. The paste formedis added to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 6.4 mm diameter, uppers bisected.

EXAMPLE 13

Preparation of 10,000 capsules each containing 25 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      2-(4-chlorophenyl)-thieno[2,3-b]pyrazolo-                                                             250.0 g                                               [3,4-d]pyridin-3(5H)--one                                                     Lactose                 1,650.0 g                                             Talcum powder           100.0 g                                               ______________________________________                                    

PROCEDURE

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance is placed in a suitable mixer and mixed firstwith the talcum, then with the lactose until homogenous. No. 3 capsulesare filled with 200 mg each, using a capsule filling machine.

Analogously tablets or capsules are prepared from the remainingcompounds of the invention, e.g. those illustrated by the examplesherein.

What is claimed is:
 1. A compound of formula IA or IB ##STR10## whereinA together with the two carbon atoms to which it is attached representsfused 2,3-, 3,4- or 4,3-pyrido wherein the carbon atoms forming saidrings are unsubstituted or one or two are substituted by lower alkyl,lower alkoxy or halogen;R₁ represents phenyl, or phenyl mono- ordisubstituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;or R₁ represents an aromatic heterocyclic radical selected from pyridyl,quinolyl, isoquinolyl, pyrimidyl and thiazolyl, or any said heterocyclicradical mono- or di-substituted by lower alkyl, lower alkoxy or halogen;R₂, R₃ and R₃ ' independently represent hydrogen or lower alkyl; or atautomer thereof; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 of formula IA or IB wherein A togetherwith the two carbon atoms to which it is attached represents fused 2,3-,3,4- or 4,3-pyrido, or any of said pyrido rings mono- or di-substitutedby lower alkyl, lower alkoxy or halogen; R₁, R₂, R₃ and R₃ ' havemeaning as given in claim 1; or a pharmaceutically acceptable saltthereof.
 3. A compound according to claim 2 of formula IA or IB whereinA together with the two carbon atoms to which it is attached representsfused 3,4- or 4,3-pyrido, or said 3,4- or 4,3-pyrido ring mono- ordi-substituted by lower alkyl, lower alkoxy or halogen; R₁, R₂, R₃ andR₃ ' have meaning as given in claim 1; or a pharmaceutically acceptablesalt thereof.
 4. A compound according to claim 3 of the formula II##STR11## wherein R₁ represents phenyl or phenyl mono- or di-substitutedby lower alkyl, lower alkoxy, halogen or trifluoromethyl; or R₁represents an aromatic heterocyclic radical selected from pyridyl,quinolyl, isoquinolyl, pyrimidyl and thiazolyl, or any said radicalmono- or disubstituted by lower alkyl, lower alkoxy or halogen; R₄ andR₅ represent independently hydrogen, lower alkyl, lower alkoxy orhalogen; or a tautomer thereof; or a pharmaceutically acceptable saltthereof.
 5. A compound according to claim 3 of the formula III ##STR12##wherein R₁ represents phenyl or phenyl mono- or di-substituted by loweralkyl, lower alkoxy, halogen or trifluoromethyl; or R₁ represents anaromatic heterocyclic radical selected from pyridyl, quinolyl,isoquinolyl, pyrimidyl and thiazolyl, or any said radical mono- ordisubstituted by lower alkyl, lower alkoxy or halogen; R₆ and R₇represent independently hydrogen, lower alkyl, lower alkoxy or halogen;or a tautomer thereof; or a pharmaceutically acceptable salt thereof. 6.A compound of claim 4 being2-phenyl-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 7. A compound of claim 4 being2-(3-pyridyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 8. A compound of claim 4 being2-(2-thiazolyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 9. A compound of claim 5 being2-p-chlorophenyl-pyrazolo[4,3-c][1,7]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 10. A compound of claim 4being 2-(2-pyrimidyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 11. A compound of claim 3being 7-methyl-2-phenylpyrazolo[4,3-c][1,8]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 12. A compound of claim 4being 2-p-chlorophenylpyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition suitable for oral or parenteral administration to mammalsfor the treatment of nervous system conditions responsive to the actionof a benzodiazepine receptor modulator, comprising an effective amountof a compound of claim 1 in combination with one or morepharmaceutically acceptable carriers.
 14. A method for treating nervoussystem diseases responsive to benzodiazepine receptor modulation inmammals which comprises administering to a mammal in need thereof aneffective amount of a compound of claim 1 or a pharmaceuticalcomposition comprising an effective amount of said compound incombination with one or more pharmaceutically acceptable carriers.